This proposal is in response to the RFA-DK02-029 "Consortium For Identification Of Environmental Triggers Of Type 1 Diabetes". Our experience in this field comes from the Diabetes Autoimmunity Study in the Young (DAISY, DK32493, M. Rewers, P.I., 7/93-6/06). DAISY began in July 1993 and allowed us to establish two unique cohorts of very young children who are at up to 20-fold increased risk of type 1 diabetes (T1DM). Prospective follow-up of these cohorts similar studies elsewhere have already provided important information concerning the natural history of b-cell autoimmunity and diabetes in early childhood, including candidate environmental triggers, but also led to the realization that definitive answers will require a large-scale collaborative effort and gave impetus to this RFA. We are proposing to address the following Specific Aims: 1. In collaboration with the other CCs and the DCC, develop standard screening and follow-up protocols to establish cohorts of 5200 general population newborns and 500 newborn relatives of T1DM patients with high-moderate genetic risk of T1DM. The intent is to follow these cohorts for islet autoantibodies and diabetes until the age of 15 years in order to identify environmental triggers of pre-diabetes and promoters of progression to diabetes. 2. Over a period of 3 years, screen in our center 30,000 general population newborns for HLA-DR,DQ genotypes associated with T1DM and enroll into the standardized prospective follow-up 500 high-risk newborns (HLA- DR3/4,DQB1*0302) and 1,200 moderate-risk newborns with no family history of TIDM. 3. Over the entire initial study period, screen in our center 1,500 newborn first-degree relatives of T1DM patients with the goal of enrolling into the standardized prospective follow-up 100 high-risk newborn relatives (HLA- DR3/4,DQBI*0302) and 100 moderate-risk newborn relatives. 4. Follow the cohorts described above until the end of the funding period and continuously (through additional competitive awards) until the age of 15 yrs to: a) further define the incidence of islet autoimmunity and diabetes by age, race/ethnicity, HLA-genotype, and family history of T1DM; b) using a case-cohort or nested case-control approach, formally evaluate candidate environmental triggers and promoters of islet autoimmunity and diabetes, e.g., early childhood diet, infections, and vaccination; c) in a very intensive follow-up from birth of the highest risk children - HLA-DR3/4,DQB1*0302 relatives carry out 'high resolution' evaluation of candidate environmental agents d) in a substudy involving pre-natally identified relatives, evaluate candidate environmental factors that may determine T1DM risk in utero. 5. To explore gene-environment interactions using combined approaches of case-control and case parent analyses. PERFORMANCESITE(S) (organization,city,state) University of Colorado Health Sciences Center, Barbara Davis Center for Childhood Diabetes Denver, Colorado KEYPERSONNEL. Seeinstructions. Usecontinuationpagesas neededto providethe requiredinformationin the formatshown below. Startwith PrincipalInvestigator.Listall other key personnelinalphabeticalorder, last namefirst. Name Organization Roleon Project Rewers, Marian J. University of Colorado P.I. Eisenbarth, George S. University of Colorado Investigator Erlich, Henry A. Roche Molecular Systems, Human Genetics Consultant Fiallo-Scharer, Rosanna University of Colorado Investigator Follensbee, Donna Independent Licensed Psychologist Consultant Gottlieb, Peter University of Colorado Investigator Lipkin, W. lan Columbia University Consultant MacKenzie, Todd University of Colorado Investigator Norris, Jill M. University of Colorado Investigator Oberste, Steven CDC, Enterovirus Reference Laboratory Consultant Pallansch, Mark CDC, Enterovirus Reference Laboratory Consultant DisclosurePermissionStatemenLApplicableto SBIR/STTROnly. See instructions. [] Yes [] No [] PHS398 (Rev.05/01) Page 2, FormPage2 [] [] Principal InvestigatodProgram Director (Last, first, middle): Rewers, Marian, J. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbe_ Face Page ....................................................................................................................................... 1 Description,